Synthetic glycerophospholipids comprising at least one reactive function, process for preparing same and uses thereof in different applications

Abstract

The present invention relates to the field of glycerophospholipids (GPL) usable for biological studies. In particular, the invention relates to novel GPL compounds comprising at least one reactive function not interfering with the biological processes, to their process of preparation and to their uses in different applications.

Description

[0001] Synthetic glycerophospholipids comprising at least one reactive function, their preparation method and their uses in different applications The present invention applies to the field of glycerophospholipids (GPL) usable for biological studies. In particular, the invention relates to new GPL compounds comprising at least one reactive function not interfering with biological processes, to their preparation method, and to their uses in different applications. Glycerophospholipids (GPL) represent the most abundant class of cellular lipids. They are also the main constituents of membrane bilayers and are involved in many cellular processes such as mobility, energy production, and intracellular trafficking. In particular, they are directly involved in many intracellular signaling pathways.They are amphiphilic lipids, meaning they have a hydrophilic part (polar head) and a hydrophobic part (apolar tail). LPGs are built around a glycerol molecule, where two hydroxyl groups are esterified with different fatty acids and the third hydroxyl group is replaced by phosphoric acid. A natural LPG in mammals can be represented by the structural formula below:. in which we distinguish a glycerol skeleton onto which are grafted: - in the so-called sn-3 position of the glycerol skeleton, a polar phosphate head, functionalized (R 1 ≠ H) or not (R 1= H), - in the so-called sn-2 position of the glycerol skeleton, an unsaturated, mono- or polyunsaturated fatty acid chain (p + q + 3 carbon atoms) (not shown), of variable length, and - in the so-called sn-1 position of the glycerol skeleton, generally a saturated fatty acid chain (n + 1 carbon atoms), of variable length. The polar phosphate head in the sn-3 position gives GPL its generic name and some of its biological properties. There are about twenty subclasses of GPL depending on the type of R group 1present on the polar head: the most abundant GPL is phosphatidylcholine (PC) which carries a choline head. Other GPLs are also naturally present such as phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (PA), and phosphatidylglycerol (PG). A cell can contain several thousand different phospholipids. Since their metabolism is rapid and often complex, it is extremely difficult to know at any given moment the location and precise role of a particular phospholipid. Research teams have therefore become interested in the synthesis of probes based on the structures of glycerophospholipids, for example containing fluorescent groups. Some of these probes are also commercially available and are shown in the diagram below.In particular, the fluorophore group (shown in a box) is added either as a replacement for part of a fatty acid chain (18:0-6:0 NBD PA and TOPFLUOR PI(4,5)P. 2 ), either on the polar phosphate head ((18:1) 2 DANSYL PS).

[0002]

[0003] . Other probes have also been described in patent application NZ577912 A. This relates to water-soluble fluorescent cell markers having the structure F-S1-S2-L, wherein F is a fluorophore, S1-S2 is a spacer arm linking F to L, L is a lipid selected from diacylated and dialkylated glycerophospholipids, and the structure F-S1-S2-L includes the following substructure -C(=R)-NH-(CH2)m-NH-C(=O)-(CH2)nC(=O)- wherein m and n are independently 3 to 6 and R is O or S. In the examples, the fluorophore is positioned at the phosphate headgroup via the S1-S2 linker spacer arm. One example has the following structure: . However, the aforementioned probes have the disadvantage of being too far removed in terms of structures from the molecules whose subcellular distribution they are supposed to illustrate.Indeed, the polar heads of glycerophospholipids ensure the specificity of the interaction with certain proteins, and the nature of the fatty acid chains also plays an important role in the functions of GPLs, and in the interactions with proteins. Therefore, any modifications in these areas (polar head or fatty acids) clearly jeopardize the recognition of GPLs by their mobilizing proteins, potentially modifying their biological functions, and thus biasing or making impossible interpretations of the experiments carried out with these probes. Moreover, these probes are synthesized with a particular fluorophore, which requires the synthesis of a new probe with a different fluorophore to vary the photophysical properties of the probe if necessary.There is therefore a need for new glycerophospholipid probes having a structure closer to that of natural GPLs, easy to prepare, and which can be used in different applications and in particular as molecular tools in the field of biology. Thus, the aim of the present invention is to overcome the drawbacks of the aforementioned prior art and to provide synthetic glycerophospholipids whose main characteristics of natural glycerophospholipids are preserved while ensuring their use as molecular tools in the field of biology. Another aim of the present invention is to provide a process for preparing such synthetic glycerophospholipids which is simple, convergent, economical, and allows access to glycerophospholipids of varied structures. The aim of the invention is achieved by the compounds and the process which will be described below.The present invention thus has as its first subject a synthetic glycerophospholipid corresponding to the following formula (I):. in which: * the OR group 1 is selected from a hydroxyl group, a choline residue, an ethanolamine residue, a glycerol residue, a serine residue, an inositol residue, an inositol monophosphate residue, an inositol bisphosphate residue, an inositol triphosphate residue, a glycerophosphate residue, a glucose residue, an inositolglycan residue, and a residue of any hydroxylated compound capable of forming a phosphodiester group in the sn-3 position belonging to a subclass of natural GPLs, * R 2 represents an unsaturated, mono- or polyunsaturated aliphatic chain, comprising at least 14 carbon atoms, and * R 3represents a saturated aliphatic chain comprising at least 10 carbon atoms. The GPLs of formula (I) of the invention respect the nature of the lipid chains (i.e. a saturated fatty acid chain in the sn-1 position and an unsaturated fatty acid chain in the sn-2 position) and of the phosphate polar head in the sn-3 position, which allows access to molecular tools with greater reliability. Furthermore, they carry a small discrete azide function in the so-called "sn-0" position which does not significantly modify their properties and can serve as a point of attachment for a marker or any biological probe, in particular by click chemistry. This discrete azide function thus makes it possible to provide suitable molecular tools for detailed exploration of the localization and the different roles in vitro, in vivo or in cellulo of GPLs.On the one hand, it does not interfere with biological processes, which should make it possible to preserve the biological properties of GPLs regardless of the lipid chains, and consequently to understand precisely the role of the different chains present in GPLs. On the other hand, this discrete azide function can then be used once the GPL of formula (I) is introduced in vitro, in cellulo or in vivo to graft different chemical tools (fluorophore, photoactivatable crosslinking agent, radiolabel, etc.) allowing biological studies without having to restart a specific synthesis of the glycerophospholipid skeleton. For the purposes of the present invention, the term "remainder" of a hydroxylated compound means the same hydroxylated compound in which the hydrogen atom has been removed from the hydroxyl function of said hydroxylated compound to form the OR group. 1 of the phosphodiester. For example, a choline residue is the OR group1 = -O-(CH2)2-N + (CH3)3, choline corresponding to the hydroxylated compound HO-(CH2)2-N + (CH3)3. As explained in the introductory part, there are about twenty subclasses of natural LPGs in mammals depending on the type of R group 1 present on the polar head. For the purposes of the present invention, the compound of formula (I) comprises two chiral centers, the first in the sn-2 position whose configuration is fixed so as to correspond to that of natural LPGs, and the second in the sn-1 position which has two possible configurations. Said compound of formula (I) can thus be chosen from a compound of formula (I)-C1, a compound of formula (I)-C2, and a mixture of the compounds of formula (I)-C1 and of formula (I)-C2, said formulas (I)-C1 and (I)-C2 being as defined below: . Preferably, the compound (I) is a compound (I)-C1. Definition of R 1 The OR group 1is preferably selected from a hydroxyl group, a choline residue, an ethanolamine residue, a glycerol residue, a serine residue, and an inositol residue. Definition of R 2 R 2 represents an unsaturated, mono- or polyunsaturated aliphatic chain comprising at least 14 carbon atoms. It preferably comprises from 16 to 24 carbon atoms, and particularly preferably from 16 to 20 carbon atoms. The unsaturated aliphatic chain may comprise from 1 to 6 unsaturations, and preferably from 1 to 3 unsaturations. Each of the unsaturations may be of Z or E configuration. The unsaturated aliphatic chain is preferably an unsubstituted unsaturated aliphatic chain. The unsaturated aliphatic chain is preferably a linear (i.e. unbranched) unsaturated aliphatic chain. Definition of R 3 R 3represents a saturated aliphatic chain comprising at least 10 carbon atoms. It preferably comprises from 14 to 30 carbon atoms, and particularly preferably from 14 to 24 carbon atoms. The saturated aliphatic chain is preferably an unsubstituted saturated aliphatic chain. The saturated aliphatic chain is preferably a linear (i.e. unbranched) saturated aliphatic chain. According to a preferred embodiment of the invention, the glycerophospholipid (GPL) is chosen from the compounds of formulae (Ia) to (Ie) presented in the following table:

[0004]

[0005] The second subject of the invention is a process for preparing an LPG of formula (I) as defined in the first subject of the invention, characterized in that it comprises at least the following steps: i) a step of preparing a phosphotriester of formula (IV) comprising a diacetal function implementing the functionalization of a diacetal derivative of (2S,3S)-butane-1,2,3,4-tetrol corresponding to formula (III) with a dialkyl halogenophosphate of formula (IV) in a basic medium, according to the following scheme: , in which R 4 represents a C1-C5 alkyl group or a benzyl group, and R 5 represents a C1-C5 alkyl group, ii) a step of deprotection in an acid medium of the diacetal function of the phosphotriester of formula (IV) to form a diol of formula (V) comprising a primary alcohol, according to the following scheme: , in which R 4is as defined in the invention, iii) a step of selective functionalization of the primary alcohol of the diol of formula (V) to form a monoalcohol of formula (VI) comprising a primary alcohol modified by a group R 6 (OR function 6 ), according to the following diagram: , in which R 4 is as defined in the invention and R 6 is selected from the following groups: tosyl, mesyl, and triflate, iv) a nucleophilic substitution step of the OR function 6 monoalcohol of formula (VI) to form an azide of formula (VII) comprising an alcohol function, according to the following scheme: , v) a step of esterification of the alcohol function of the azide of formula (VII) with a saturated fatty acid of formula (VIII) to form an azide of formula (IX) comprising a saturated fatty acid chain and an alcohol function protected by a paramethoxybenzyl (PMB) group, according to the following scheme: , in which R 3 and R 4 are as defined in the invention, vi) a step comprising a sub-step vi-1) of deprotection of the paramethoxybenzyl group of the azide of formula (IX) to form an azide of formula (X) comprising an alcohol function, followed by a sub-step vi-2) of esterification of the alcohol function of the azide of formula (X) with an unsaturated fatty acid of formula (XI), to form an azide of formula (XII) comprising a saturated fatty acid chain, an unsaturated fatty acid chain, and a phosphotriester function, according to the following scheme: , in which R 2 is as defined in the invention, and vii) a step of deprotection of the R groups 4 to form a compound of formula (I) in which OR 1 = OH, optionally followed by a step of preparing a compound of formula (I) in which OR 1≠ OH. The process of the invention allows easy access to LPGs of formula (I) according to a convergent synthesis route using a synthesis intermediate of formula (VII) common to all LPGs of formula (I). Consequently, the regio- and stereo-selective introduction of the saturated and unsaturated fatty acid chains is carried out as late as possible, i.e. during the two penultimate steps. This is all the more important for the introduction of the unsaturated fatty acid chain since the unsaturations can be sensitive to certain reaction conditions and / or oxidize easily. The paramethoxybenzyl (PMB) group in particular makes it possible to protect the alcohol function in the sn-2 position throughout the process of the invention until the introduction of the unsaturated fatty acid chain. Furthermore, the deprotection of the phosphate group by the R groups 4is carried out in a final step in order to facilitate purifications and / or to avoid the formation of secondary products during the previous steps. Step i) Step i) is a step of preparing a phosphotriester of formula (IV) comprising a diacetal function implementing the functionalization of a diacetal derivative of (2S,3S)-butane-1,2,3,4-tetrol corresponding to formula (III) with a dialkyl halogenophosphate of formula (IV) in a basic medium. In particular, the diacetal derivative of (2S,3S)-butane-1,2,3,4-tetrol corresponding to formula (III) which is used in step i) already has the correct stereochemistry on the sn-2 position to access the LPGs of formula (I). This stereochemistry is preserved throughout the process of the invention. Step i) allows the introduction of a protected phosphate function in position sn-3 of the diacetal derivative (III).This step i) is carried out in a basic medium, for example in the presence of a base chosen from potassium tert-butanolate (tBuOK), NaH, NaNH2, and KH. Step i) is preferably carried out at a temperature ranging from -20°C to 50°C. Step i) may be carried out in a solvent such as dichloromethane, tetrahydrofuran (THF) or toluene. The dialkyl halogenophosphate of formula (IV) is preferably chosen from dialkyl chlorophosphates such as dimethylchlorophosphate. R. 4 preferably represents a methyl group. R 5preferably represents a methyl group. Step ii) Step ii) is a step of deprotection in an acid medium of the diacetal function of the phosphotriester of formula (IV) to form a diol of formula (V) comprising a primary alcohol function. During this step ii), two alcohol functions are obtained including a primary alcohol function in the sn-0 position. This step ii) can be carried out in a solvent chosen from lower alcohols (i.e. C1-C4), such as methanol, ethanol, or isopropanol. Step ii) is carried out in the presence of an acid chosen from hydrochloric acid (HCl), and any other suitable acid. According to a preferred embodiment, step ii) is carried out by acid methanolysis, in the presence of HCl. Step ii) is preferably carried out at room temperature (i.e. 18-25°C).Step iii) Step iii) is a step of selective protection of the primary alcohol function of the diol of formula (V) to form a monoalcohol of formula (VI) comprising a primary alcohol function protected by an R group. 6 . Step iii) is preferably carried out in the presence of a compound R 6 Y, Y being a halogen atom selected from chlorine, bromine and iodine. Step iii) is preferably carried out in the presence of a base, and optionally a catalyst. The base may be selected from diisopropylethylamine (DIPEA), triethylamine (TEA), potassium carbonate (K2CO3), sodium hydroxide (NaOH), and potassium hydroxide (KOH). The catalyst may be selected from tin-based catalysts such as Bu2SnO. The group R 6is preferably a tosyl group. Y is preferably a chlorine atom. In a preferred embodiment, step iii) is carried out in the presence of tosylate chloride, a base, and a tin-based catalyst. Step iii) may be carried out in an aprotic solvent such as toluene. Step iii) is preferably carried out at room temperature (i.e. 18-25°C). Step iv) Step iv) is a step of nucleophilic substitution of the primary alcohol function protected by an R group 6 monoalcohol of formula (VI) to form an azide of formula (VII) comprising an alcohol function. This step iv) allows the introduction of the azide function thanks to the displacement of the -OR group 6by nucleophilic substitution. Step iv) is preferably carried out in the presence of an azide compound selected from sodium azide, potassium azide, tetrabutylammonium iodide, diphenylphosphoryl azide, and trimethylsilyl azide. Step iv) is preferably carried out at a temperature ranging from 0°C to 100°C. Step iv) is generally carried out in a polar solvent, preferably capable of solubilizing the azide salts, such as dimethylformamide (DMF). This azide of formula (VII) is a key intermediate compound in the synthesis of synthetic LPGs of formula (I). Thanks to it, LPGs carrying various fatty acid chains in sn-1 and sn-2 positions can be obtained in only three steps. At the end of step iv), the crude reaction product may comprise the azide of formula (VII) in a mixture with the azide of formula (VII') following: , in which the phosphate triester has been partially deprotected (deprotection of an R group 4 ). The yield of this step iv) can be improved by treating the crude reaction product obtained at the end of step iv) with a diazomethane derivative such as trimethylsilyldiazomethane, 1-(mesitylene-2-sulfonyl)-3-nitro-1H-1,2,4-triazole, SiO2Cl, CsF / MeI, or trimethylorthoformate; and an alcohol R 4 OH, R 4being as defined in the invention, in order to lead to the azide of formula (VII). Step v) is a step of esterification of the alcohol function of the azide of formula (VII) with a saturated fatty acid of formula (VIII) to form an azide of formula (IX) comprising a saturated fatty acid chain of formula and an alcohol function protected by a paramethoxybenzyl (PMB) group. This step v) can use a coupling agent, in particular chosen from carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), or N,N'-diisopropylcarbodiimide (DIC); and optionally a catalyst such as dimethylamidopyridine (DMAP), or pyridine. Step v) is generally carried out in a non-nucleophilic solvent such as dichloromethane, or chloroform. Step v) is preferably carried out at room temperature (i.e. 18-25°C).The fatty acid of formula (VIII) may be chosen from stearic acid, caproic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, and melissic acid. Step vi) Step vi) comprises a sub-step vi-1) of deprotection of the paramethoxybenzyl group of the azide of formula (IX) to form an azide of formula (X) comprising an alcohol function, followed by a sub-step vi-2) of esterification of the alcohol function of the azide of formula (X) with an unsaturated fatty acid of formula (XI), to form an azide of formula (XII) comprising a saturated fatty acid chain, an unsaturated fatty acid chain, and a phosphotriester function.Substep vi-1) may be carried out in the presence of a deprotection agent selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), cerium ammonium nitrate (CAN), aluminum trichloride (AlCl3) in the presence of ethane thiol (EtSH), tin tetrachloride (SnCl4) in the presence of phenyl thiol (PhSH), or cerium trichloride (CeCl3) in the presence of sodium iodide (NaI). Substep vi-1) is preferably carried out in a biphasic solvent mixture such as a mixture of dichloromethane and water. Substep vi-1) is preferably carried out at a temperature ranging from -20°C to 50°C. In a preferred embodiment, sub-step vi-1) is carried out in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and at a temperature ranging from -20°C to 50°C. At the end of sub-step vi-1), the alcohol of formula (X) obtained is directly used in sub-step vi-2), in particular without a purification step and immediately.This thus prevents its degradation. Sub-step vi-2) may use a coupling agent, in particular chosen from carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), or N,N'-diisopropylcarbodiimide (DIC); and optionally a catalyst such as dimethylamidopyridine (DMAP), or pyridine. Sub-step vi-2) is generally carried out in a non-nucleophilic solvent such as dichloromethane, or chloroform. Sub-step vi-2) is preferably carried out at a temperature ranging from -25°C to 0°C.The fatty acid of formula (XI) may be selected from oleic acid, linoleic acid, lauroleic acid, myristoleic acid, palmitoleic acid, vaccenic acid, gadoleic acid, ketoleic acid, erucic acid, selacholeic acid, linolenic acid, eleostearic acid, arachidonic acid, cuplanodonic acid, elaidic acid, and petroselinic acid. The temperature ranges of sub-steps vi-1) and vi-2) as well as the implementation of sub-step vi-2) directly after sub-step vi-1) make it possible to promote the deprotection of the PMB group while avoiding the reaction of the ester carried by the azide of formula (X) on itself by an intramolecular trans-esterification mechanism which would then induce a loss of regioselectivity in the localization of the fatty acid chains which can be followed by phosphorus NMR. Step vii) Step vii) consists of the deprotection of the R groups. 4to form a compound of formula (I) in which OR 1 = OH, optionally followed by a step of preparing a compound of formula (I) in which OR 1 ≠ OH Deprotection of R groups 4 can be carried out in the presence of a reagent selected from bromotrimethylsilane, butylamine, ammonia, trimethylamine, triethylamine, boron tribromide (BBr3), pyridine, sodium iodide (NaI), and lithium cyanide (LiCN). Step vii) is preferably carried out in a solvent such as chloroform, DMF, or toluene. Step vii) is preferably carried out at room temperature (i.e. 18-25°C). At the end of step vii), an LPG of formula (I) comprising a polar phosphate head (R 1 = H) is obtained. The diacetal derivative of (2S,3S)-butane-1,2,3,4-tetrol of formula (III) as used in step i) can be prepared from a dialkyl-L-tartrate of the following formula (XIII): in which R7 is a C1-C5 alkyl group, and preferably a methyl group. In particular, the diacetal derivative (III) can be obtained according to a method similar to that described by Namysio et al., J. Prakt. Chem., 1999, 341, 6, 557-561. According to a particularly preferred embodiment of the invention, the diacetal derivative (III) is obtained according to the steps described in the following scheme:

[0006] with R 5 being as defined above. This method includes in particular the protection of dimethyl-L-tartrate in the form of a diacetal followed by two successive reductions of the esters and the opening of the acetal to form a triol whose two adjacent alcohol functions are then protected by a dialkylketal. The diacetal derivative (III) can also be obtained according to the steps described in the following scheme:

[0007] with R 5being as defined above. This method comprises in particular the selective monoprotection of dimethyl-L-tartrate followed by two successive reductions of the esters and the protection by a dialkylketal of the two adjacent alcohol functions. The third subject of the invention is a modified glycerophospholipid corresponding to the following formula (XIV): in which: * OR' 1 represents an OR group 1 as defined in the invention or a photoactivatable group, * R 2 and R 3 are as defined in the first subject of the invention, and * R 8 and R 9 , independently of each other, are selected from a fluorophore group, a photocrosslinkable group, a radiolabel group, and a hydrogen atom; or the R groups 8 and R 9together form a group selected from a fluorophore group, a photocrosslinkable group, and a radiolabel group. The modified GPLs of formula (XIV) retain the structure and stereochemistry of natural GPLs. The fluorophore group may be selected from nitrobenzooxadiazole (NBD)-based fluorophores, xanthene-based fluorophores, carborhodamines, cyanines, coumarins, and polycyclic aromatic hydrocarbons such as pyrenes or porphyrins. Coumarins, nitrobenzooxadiazole (NBD)-based fluorophores, and carborhodamines are preferred. Examples of fluorophore groups that can be used according to the invention include the Alexa Fluor range of fluorophores marketed by Molecular Probes. The photocrosslinkable group as R 8 and / or R 9, may comprise (or consist of) an aryl azide group, a diazirine group, a diazo group, a benzophenone group, a benzophenone-derived group, a tetrazole group, or a quinoxalinone group. The radiolabel group may comprise (or consist of) fluorine-18, carbon-11, iodine-123, iodine-124, or a complex of gallium-67, indium-111m, technetium-99m, or thallium-201. Preferably, R 8 is a hydrogen atom and R 9 is a fluorophore group, R 9 is a hydrogen atom and R 8 is a fluorophore group, or the R groups 8 and R 9 together form a fluorophore group. The photoactivatable group as OR' 1may comprise an aromatic group containing one or more nitro-NO2 functions such as an orthonitrobenzyl or orthonitroindoline group, a coumarin group such as a coumarin-4-yl group, or a quinoline group. The fourth subject of the invention is a process for preparing a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention, characterized in that it comprises at least one step A) of bringing into contact a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a process as defined in the second subject of the invention, with an alkyne corresponding to the following formula (XV): in which R 8 and R 9are as defined in the invention. Step A) may be carried out by Huisgen cycloaddition, by Huisgen cycloaddition catalyzed by copper salts (CuAAC), or by Huisgen cycloaddition using a strained alkyne (SPAAC). Huisgen cycloaddition using a strained alkyne (SPAAC) is preferred. This synthetic route makes it possible in particular to overcome the cytotoxicity of copper. The alkyne of formula (XV) is preferably a strained alkyne, in particular comprising a cyclooctyne group such as a difluorocyclooctyne group (DIFO), a difluorobenzocyclooctyne group (DIFBO), a dibenzocyclooctyne group (DIBO), a biarylazacyclooctynone group (BARAC), or a bicyclo[6.1.0]nonyne group (BCN).As an example of a constrained alkyne of formula (XV) and comprising a cyclooctyne group, mention may be made of the following compound (XVa) comprising nitrobenzodiazole as fluorophore and a DIBO group as constrained alkyne: or the following compound (XVa-2) comprising carborhodamine as fluorophore and a DIBO group as constrained alkyne:. . Step A) can be carried out before or after bringing the synthetic LPG (I) into contact with a biological medium, and preferably after bringing the synthetic LPG (I) into contact with a biological medium. According to a preferred embodiment of the invention, step A) is carried out after bringing the synthetic LPG (I) into contact with a biological medium. According to a particularly preferred embodiment of the invention, the method then further comprises, before step A), a step a) of bringing the synthetic LPG (I) into contact with a biological medium, in particular in vitro, in vivo, ex vivo or in cellulo, and preferably in vitro or ex vivo. Consequently, it is possible to address the synthetic LPG (I) into a cell, then to incorporate on the glycerol backbone according to step A) different functional groups, which will in particular depend on the intended application. When R' 1is a photoactivatable group, said group can be introduced before or after step A). ​​The process ensures the preservation of the structure and stereochemistry of natural GPLs, of the unmodified polar head, possibly caged by a photolabile group to avoid their metabolism before the biological study, and of the intact and correctly positioned fatty acid chains. In addition, a single synthetic GPL (I) allows access to several types of modified GPLs (XIV) and thus to access varied applications for a single synthetic GPL (I) prepared. This thus makes it possible to obtain modified GPLs (XIV) with greater structural proximity compared to natural GPLs and to have great flexibility and diversity in the choice of tools for biological studies.The fifth subject of the invention is the use of a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a method as defined in the second subject of the invention; or of a modified glycerophospholipid (XIV) as defined in the third subject of the invention or obtained according to a method as defined in the fourth subject of the invention, as a molecular tool, in particular in the field of biology, or as a biological probe, in particular for biological studies. These synthetic glycerophospholipids of formula (I) and modified glycerophospholipids of formula (XIV) can for example be used to understand the cellular processes and / or the biological functions of natural GPLs according to the types of polar head and / or fatty acid chains present in said GPLs.In particular, it has been shown that synthetic GPLs of formula (I) can interact just like natural GPLs with mobilizing proteins such as Spo20p-GFP which is fluorescent in green (see example 3 of the application below), or chromogranin A (or CgA). In particular, it has been shown that modified GPLs of formula (XIV) can interact just like natural GPLs with mobilizing proteins such as chromogranin A (or CgA). GPLs (I) and (XIV) can be used in the form of a kit for assaying and / or localizing biomolecules, such as proteins.The sixth subject of the invention is the use of a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a method as defined in the second subject of the invention; or of a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention or obtained according to a method as defined in the fourth subject of the invention, as a diagnostic tool, and preferably as an in vitro or ex vivo diagnostic tool. In vitro diagnosis is carried out outside the human body on a biological medium. Ex vivo diagnosis is carried out outside the human body on a biological medium which has undergone prior treatment before use.In other words, the invention relates to a method implementing the contacting of a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a method as defined in the second subject of the invention; or of a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention or obtained according to a method as defined in the fourth subject of the invention, with a biological medium for diagnosis, and in particular for locating and / or identifying the different proteins which interact with it.The seventh subject of the invention is a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a process as defined in the second subject of the invention; or a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention or obtained according to a process as defined in the fourth subject of the invention, for its medical use. In other words, the invention relates to the use of a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a process as defined in the second subject of the invention; or a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention or obtained according to a process as defined in the fourth subject of the invention, for obtaining or preparing a medicament intended for therapeutic use (i.e.for obtaining or preparing a medicament for a therapeutic treatment). The invention also relates to a treatment method comprising the administration of a synthetic glycerophospholipid of formula (I) as defined in the first subject of the invention or obtained according to a method as defined in the second subject of the invention; or a modified glycerophospholipid of formula (XIV) as defined in the third subject of the invention or obtained according to a method as defined in the fourth subject of the invention, in particular in a therapeutic quantity, to a patient. In particular, GPLs (I) and (XIV) comprising three successive unsaturations on the unsaturated fatty acid chain can be used to improve the secretion of neurotransmitters by neurosecretory cells and / or to treat diseases of the nervous system, in particular linked to normal or pathological aging, or linked to mental retardation (Fragile X, Coffin Lowry Syndrome).Brief description of the drawings The attached drawings illustrate the invention: Figure 1 represents confocal microscopy images of media comprising different GPLs incubated with PC12 cells expressing Spo20p-GFP. Figure 2 represents the percentage of colocalization of the Spo20p-GFP protein and different GPLs at the plasma membrane. Figure 3 represents light microscopy images of liposomes containing different GPLs. Figure 4 shows confocal microscopy images of liposomes containing different GPLs. Figure 5 shows confocal microscopy images of liposomes containing different GPLs incubated with a GgA-AF633 protein. Other characteristics, variants and advantages of the use, of the phytotoxic composition, or of the method according to the invention will emerge more clearly upon reading the exemplary embodiments which follow, given by way of illustration and not limitation of the invention.Examples The reagents were commercially sourced (Sigma-Aldrich, Acros, Alfa-Aesar) as well as the solvents (Sigma-Aldrich, Acros) and were used as received from the manufacturers without specific treatment unless otherwise indicated. The nuclear magnetic resonance (NMR) experiments were conducted using a spectrometer sold under the trade name Avance DPX300 by Bruker operating at 293°K with a frequency of 300.13 MHz for proton NMR (. 1 H), 121.442 MHz for phosphorus NMR ( 31 P) and 75.48 MHz for carbon NMR ( 13C). Chemical shifts are expressed in ppm (parts per million) compared to an internal reference, tetramethylsilane (TMS, δ= 0 ppm) and internal calibrations are performed using a residual solvent signal. Proton NMR coupling constants are reported in hertz and multiplicities are specified (s: singlet; d: doublet; t: triplet; m: multiplet; dd: doublet of doublet). Electrospray ionization mass spectrometry (ESI-MS) data were acquired using a spectrometer sold under the trade name LCT Premier XE by Waters Acquity. Accurate mass measurements (HRMS) were performed with a Synapt G2 HDMS system and an electrospray source equipped with a lockspray® system. Experiments were performed with a Waters Acquity BEH positively charged C18 reference column with the following specificities: 1.7 µm; 2.1-50 mm. The gradient used is: 98% / 2% H2 O / ACN to 100% ACN in 4 min and 1.3 min to 100% ACN with a flow rate of 0.25 ml.min −1 . 0.5 ml are injected, and the source temperature is set at 120°C and the desolvation temperature at 300°C, with voltages of 2200 V for the detector and 3000 V for the capillary. Ultra high performance liquid chromatography (UHPLC) analyses were recorded on a device sold under the trade name Ultimate 3000 by Thermo Fisher. The experiments were carried out on a Hypersil GOLD reference C18 column with the following specifications: 3 µm; 2.1 - 50 mm. The gradient used is as follows: 95% / 5% ACN / H2O to 100% H2O in 6 min with a flow rate of 0.6 ml.min −1and a pressure of 450 Bar. 10 µL are injected and an oven temperature is set at 25 °C. The products were analyzed with a UV detector at 254 nm and 270 nm. Elemental analyses were recorded on a device sold under the trade name Flash 2000 by Thermo Fisher - EAGER 300. The determination of the general formula of an organic compound by the mass percentage of each of the elements (C, H, N, S) present in said compound is obtained by integrating the chromatography peaks of each of the elements. The surfaces thus integrated are pointed on a calibration line in order to determine the concentration of each of the elements. The results are provided with an absolute precision of 0.4%. Each sample is weighed precisely in a tin basket. The standard used for the calibration range is 2,5-Bis(5-tert-butyl-benzoxazol-2-yl)thiophene (BBOT) with the following composition: %C: 72.53; %H: 6.09; %N: 6.51; %S: 7.44.Infrared spectra were taken with a spectrophotometer sold under the trade name Perkin Elmer 100 FTIR (attenuated total reflectance or ATR technique using a diamond as a crystal). The products are analyzed directly on the diamond. The absorption bands are expressed in cm. −1. Example 1: Synthesis of Compound Ia Preparation of the LPG Precursor (S)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(4-methoxybenzyloxy)ethan-1-ol (S)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(4-methoxybenzyloxy)ethan-1-ol was prepared according to the 5 steps illustrated in the following scheme: First step: The first step is a reaction to convert the aldehyde to the diacetal. 78.5 g of p-methoxybenzaldehyde (580 mmol, 70 ml) and 61.5 g of trimethylorthoformate (580 mmol, 68.1 ml, 1 equiv.) were stirred vigorously for 5 min in 25 ml of methanol (MeOH). Then, 4 drops of 37% HCl were added, the translucent orange mixture turned to translucent pink and the solution was stirred vigorously overnight. Then, 450 mg of K2CO3 was added and the resulting mixture was stirred vigorously for 1 h. The color of the mixture changed from translucent pink to translucent yellow.300 ml of petroleum ether are then added and the formation of a bright white cloudy suspension is observed. The resulting mixture is filtered and the solvents are evaporated under reduced pressure. The crude product is distilled under vacuum (5 mbar, TEboiling point = 97 °C) to obtain 1-(dimethoxymethyl)-4-methoxybenzene in the form of a colorless liquid with a yield of 93% (97.7 g, 536 mmol). Formula: C10H14O3, Molar mass = 182.22 g mol. −1. Second step: The second step is a protection step of dimethyl L-tartrate in acetal form. 40 g of dimethyl L-tartrate (225 mmol, compound (XIIIa)) and 46 g of 1-(dimethoxymethyl)-4-methoxybenzene as prepared in the previous step (337.5 mmol, 64.5 ml 1.5 equiv.) were added into 500 ml of dry toluene under inert atmosphere. The solution was stirred vigorously and 400 mg of paratoluene sulfonic acid (PTSA) (2.3 mmol, 0.01 equiv.) was added and the methanol formed during the reaction was evaporated by distillation. The color of the solution changed from translucent purple pink to orange and the distillation process was stopped once the distillate reached the temperature of 110°C. The crude mixture is cooled to room temperature and 250 ml of dichloromethane (CH2Cl2 or DCM) is added, then the reaction is stopped with an excess of K2CO3. The crude mixture is stirred for another hour to obtain a yellow colored mixture.The crude mixture is filtered and the solvents are evaporated under reduced pressure to obtain a light yellow solid which is purified by chromatography with silica gel (eluent: petroleum ether + 0.1% triethylamine (Et. 3 N) / ethyl acetate (AcOEt) ). This purification step can be replaced by washing the light yellow solid with cyclohexane. In both cases, a white solid is obtained with a yield of 90% corresponding to (4R,5R)-dimethyl-2-(4-methoxyphenyl)-1,3-dioxolane-4,5-dicarboxylate (60 g, 202.5 mmol). Formula: C14H16O7, Molar mass = 296.27 g mol −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 3.81, 3.84 and 3.87 (9H, OCH3); 4.84 (d, J=4.0 Hz, 1H, CH(OR)); 4.95 (d, J = 4.0 Hz, 1H, CH(OR)); 6.09 (s, 1H,CH(OR)2); 6.92 (d, J = 8.8 Hz, 2H, aromatic CH); 7.51 (d, J= 8.7 Hz, 2H, CH aromatic). NMR 13C (75.49 MHz, CDCl3), δ (ppm): 52.6, 52.7 and 55.1 (3C, OCH3); 76.9, 77.1 (CH(OR)); 106.5 (CH(OR)2); 113.6, 127.2, 128.5 and 160.8 (6C, aromatic C); 169.4 and 169.9 (2C, CO2R). Third step: The third step is a reduction step of the ester functions into alcohol functions. 46 g (160 mmol) of the diester as prepared in the previous step are solubilized in 750 ml of methanol under an inert atmosphere. The resulting mixture is stirred at 0°C and 18.2 g (480 mmol, 3 equiv.) of NaBH4 are added portionwise. The resulting mixture is stirred for 3 hours at room temperature. The solvent is then evaporated under reduced pressure. 500 ml of ethyl acetate is added and the resulting organic solution is washed with 200 ml of brine. The aqueous phase is extracted with 500 ml of ethyl acetate. The organic phases are combined and dried over MgSO4, filtered and the solvent is evaporated under reduced pressure.The product corresponding to (4S,5S)-2-(4-methoxyphenyl)-1,3-dioxolane-4,5-diyl) dimethanol is obtained in the form of a white solid without purification with a yield of 98% (23.1 g, 96 mmol). Formula: C12H16O5, Molar mass = 240.25 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 2.02 (bs, 2H, OH); 3.82 (s, 3H, OCH3); 3.90 (4H, CH 2 OH) ; 4.16 (m, 2H, CH(OR)); 5.95 (s, 1H, CH(OR) 2 ); 6.92 (d, J = 8.8 Hz, 2H, aromatic CH); 7.51 (d, J = 8.7 Hz, 2H, aromatic CH). NMR 13 C (75.49 MHz, CDCl3), δ (ppm): 55.4 (OCH3); 62.4 and 62.5 (CH2OH); 78.6 and 79.4 (CH(OR)); 103.8 (CH(GOLD) 2); 113.9, 128.1, 129.4 and 160.7 (6C, aromatic C). Fourth step: The fourth step is an acetal opening step to form a triol whose sn-1 position is released while the sn-2 position is still protected. 30 g (125 mmol) of the diol prepared in the previous step is solubilized in 750 ml of dry tetrahydrofuran (THF) under an inert atmosphere. The resulting mixture is cooled to 0°C and 83.1 ml (291.2 mmol, 7 equiv.) of BH3·Me2S is added dropwise at 0°C. The resulting mixture is stirred for 30 min at room temperature and then for 3 h at 75°C. The resulting mixture is cooled to 0°C and the excess borane is gently hydrolyzed with methanol. The resulting mixture is stirred for 30 min at room temperature and the solvents are evaporated under reduced pressure. The residue is treated twice more with 250 ml of methanol and evaporated under reduced pressure.The crude solid obtained is extracted twice with CH2Cl2 and the insoluble white solid containing the boron salts is filtered. The organic phases are recovered, evaporated and the resulting product is purified by chromatography on silica gel (eluent: AcOEt / MeOH + 0.1% Et3N). This purification step can be replaced by recrystallization from toluene. In both cases, the product corresponding to (2S,3S)-3-(4-methoxybenzyloxy)-butan-1,2,4-triol is obtained in the form of a white solid with a yield of 58% (17.5 g, 72.28 mmol). Formula: C12H18O5, Molar mass = 242.27 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 2.42-2.77 (3H, OH); 3.54-3.59 (m, 3H, CH(OR), CH2OH); 3.68-3.89 (m, 3H, CH2OH, CH(OH)); 3.76 (s, 3H, OCH3); 4.52-4.65 (2d, J=11.3 Hz, 2H, benzyl CH 2 ); 6.90 (d, J = 8.7 Hz, 2H, aromatic CH); 7.27 (d, J= 8.7 Hz, 2H, aromatic CH). NMR 13C (75.49 MHz, CDCl3), δ (ppm): 55.4 (OCH3); 60.8 and 63.4 (2C, CH2OH); 72.1 (CH(OH)); 72.3 (benzyl CH 2); 79.0 (CH(OR)); 114.1, 129.6, 129.8 and 159.6 (6C, aromatic C). Fifth step: The fifth step is a protection reaction of the two alcohol functions in the form of a dimethylacetal. 14 g of triol as prepared in the previous step (58.6 mmol) are solubilized in dry acetone (145 ml) under an inert atmosphere. Then, 21.6 ml (175.8 mmol, 3 equiv.) of dimethoxypropane and 500 mg (2.9 mmol, 5 mol.%) of paratoluenesulfonic acid (PTSA) are added and the resulting mixture is stirred for 1 h. The color of the mixture changes from translucent to red-brown. 460 ml (3.3 mmol) of triethylamine are added and the color changes to translucent yellow. The solvents are evaporated under reduced pressure and the crude product is purified by chromatography on silica gel (eluent: petroleum ether + 0.1% triethylamine / EtOAc).The obtained compound (IIIa) corresponding to (S)-2-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-(4-methoxybenzyloxy)ethan-1-ol is obtained in the form of a light yellow translucent oil with a yield of 70% (11.53g, 40.9 mmol). Formula: C15H22O5, Molar mass = 282.27 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 1.36 and 1.42 (3H each, CH3); 2.19 (1H each, OH); 3.55 (m, 2H, CH2OH); 3.65 (m, 1H, CH(OPMB)); 3.70 (m, 1H, dioxolane CH2(OR)); 3.80 (s, 3H, OCH3); 4.00 (dd, J= 8.3 Hz; 6.4 Hz, 1H, dioxolane CH2(OR)); 4.28 (dt, J = 8.3 Hz; 6.4 Hz, 1H, dioxolane CH(OR)); 4.59-4.72 (2d, J=11.5 Hz, 2H, benzyl CH2); 6.89 (d, J = 8.6 Hz, 2H, aromatic CH); 7.27 (d, J = 8.6 Hz, 2H, aromatic CH). NMR 13C (75.49 MHz, CDCl3), δ (ppm): 25.4 and 26.5 (CH3); 55.4 (OCH3) ; 61.8 (CH2OH) ; 65.7 (dioxolane CH2) ; 72.6 (benzyl CH2); 76.8 (CH dioxolane) 78.9 (CH(OPMB)) ; 109.6 (dioxolane C(OR)2(Me)2) ; 114.1 , 129.6 , 129.8 and 159.6 (6C, C aromatic). HRMS (ESI+) m / z calcd. For [C 15 H 22 THEIR 5 ] [M+NH 4 ] + : 300.1805 ; found : 300.1815. IR (ν cm −1 ) : 826 (ν p-disubst. benzene) ; 1032 (ν CH2OH) ; 1110 - 1140 (ν alkyl ethers) ; 1247 (ν C=COC) ; 1370 (ν C-(CH 3 ) 2 ) ; 1375 - 1385 (ν C-CH 3 ) ; 1590 - 1615 (ν aryl) ; 2815 - 2835 (ν O-CH3) Preparation of LPG (Ia) First step: The first step is a functionalization of the alcohol function in the sn-3 position of the diacetal (IIIa) to form a phosphotriester (IVa). 6 g (21.24 mmol) of the diacetal (IIIa) as prepared in the previous step are solubilized in 90 ml of dry DCM under an inert atmosphere. The resulting mixture is cooled to 0°C. Then, 2.98 g (26.58 mmol, 1.25 equiv.) of freshly sublimed potassium tert-butanolate are added. The resulting mixture is stirred and the color of the mixture turns yellow. 2.86 ml (26.58 mmol, 1.2 equiv.) of freshly distilled dimethylchlorophosphate (IIa) are added dropwise at 0°C, the resulting mixture is stirred for 4 h at 0°C. Then, 72 ml of saturated NaHCO3 solution is added and the resulting mixture is stirred for 1 h. The organic phase is separated and the aqueous phase is extracted twice with 180 ml of DCM.The organic phases are combined and washed twice with 60 mL of saturated NaHCO3 solution, dried, and the solvents are evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: petroleum ether + 0.1% triethylamine / EtOAc). Compound (IVa) corresponding to [(S)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-((4-methoxybenzyl)oxy]ethyl dimethyl phosphate is obtained in the form of a translucent light yellow oil with a yield of 60% (4.93 g, 12.6 mmol). Formula: C17H27O8P, Molar mass = 390.37 g mol. −1 . NMR 1H (300.13 MHz, CDCl3), δ (ppm) : 1.34 and 1.41 (3H each, CH3); 3.65 (m, 1H, dioxolane CH(OR)) ; 3.67 (m, 1H, dioxolane CH2(OR)); 3.74 and 3.78 (s, 3H each, P-OCH3) ; 3.80 (s, 3H, benzyl-OCH3) ; 3.95-4.05 (dd, J= 8.4Hz ; 6.6 Hz, 1H, dioxolane CH2(OR)) ; 4,14-4,27 (m, 3H, CH2 OP(O)(OCH3)2, CH(OPMB)) ; 4.59-4.72 (2d, J= 11.3 Hz, 2H, benzyl CH2) ; 6.87 (d, J = 8.7 Hz, 2H, aromatic CH); 7.28 (d, J= 8.6 Hz, 2H, aromatic CH). NMR 31 P (121.442 MHz, CDCl 3 ), δ (ppm) : 1.27 (P(O)(OMe) 2 ) NMR 13 C (75.49 MHz, CDCl3), δ (ppm) : 25.4 and 26.5 (CH3) ; 54.5 and 54.6 (2d, J= 6.0 Hz, -P(O)(OCH3)2) ; 55.4 (benzyl-OCH3) ; 65.5 (dioxolane CH2); 67.0 (d, J= 6.0 Hz, CH 2 -OP(O)(OCH 3 ) 2 ) ; 72.8 (benzyl CH 2 ) ; 75.7 (CH(OPMB)); 77.1 (dioxolane CH); 109.6 (dioxolane C(OR)2(Me)2) ; 113.9 , 129.7 , 130.1 and 159.5 (6C, C aromatic). HRMS (ESI+) m / z calcd. For [C17H27O8P] [M+H] +: 391.1522; found: 391.1534. IR (ν cm −1): 820 (ν p-disubst. benzene); 1025 (ν PO-(C)); 1110 - 1140 (ν alkyl ethers); 1214 (ν C=COC); 1247,13 (ν P=O); 1360 - 1370 (ν C-CH3)2)); 1375 - 1385 (ν C-CH3); 1590 - 1615 (ν aryl); 2815 - 2835 (ν O-CH3); 3015 (ν=CH aryl) Second step: The second step is a deprotection step of the alcohol functions in sn-1 and sn-0 positions. 3.7 g (9.5 mmol) of diacetal (IVa) as prepared in the previous step are dissolved in 100 ml of dry methanol. 1.85 ml of 1M HCl are added dropwise and the resulting mixture is stirred for 8 h at room temperature. 350 mg of solid NaHCO3 are added and the resulting mixture is stirred for 15 min. The solvent is evaporated under reduced pressure. 150 ml of DCM are added and the mixture is filtered. The solvent is evaporated under reduced pressure and a translucent oil is obtained. The crude product is purified by chromatography on silica gel (eluent: EtOAc / MeOH).The product (Va) corresponding to (2S,3S)-3,4-dihydroxy-2-((4-methoxybenzyl)oxy)butyl dimethyl phosphate is obtained in the form of a translucent light yellow oil with a yield of 82% (2.8g, 8.0 mmol). Formula: C14H23O8P, Molar mass = 350.30 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 2.37 (2H, OH); 3.65 (2H, CH2OH); 3.70 (1H, CH(OPMB)); 3.73 (1H, CH(OH)); 3.75 and 3.79 (s, 3H each, P-OCH3); 3.81 (s, 3H, benzyl OCH3); 4.13-4.30 (2m, 2H, CH2 OP(O)(OCH3)2); 4.48-4.72 (2d, J=11.3 Hz, 2H, benzyl CH2); 6.88 (d, J = 8.7 Hz, 2H, CH aromatic); 7.27 (d, J= 8.6 Hz, 2H, CH aromatic). NMR 31 P (121.442 MHz, CDCl3), δ (ppm): 1.51 (P(O)(OMe)2). NMR 13 C (75.49 MHz, CDCl3), δ (ppm): 54.5 and 54.6 (2d, J= 6.0 Hz, - P(O)(OCH 3 ) 2 ); 55.4 (benzyl OCH 3 ); 63.4 (CH 2 OH); 66.2 (d, J= 6.0 Hz, CH 2- OP(O)(OCH3)2); 70.9 (CH(OH)); 72.9 (benzyl CH2); 77.4 (CH(OPMB)); 114.0, 129.6, 129.9 and 159.5 (6C, aromatic C). HRMS (ESI+) m / z calcd. For [C14H23O8P] [M+H] + : 351.1209; found: 351.1223. IR (ν cm −1): 820 (ν p-disubst. benzene); 1031.76 (ν PO-(C)); 1110 - 1140 (ν alkyls ethers); 1180.02 (ν C=COC); 1248.02 (ν P=O); 1375 - 1385 (ν C- CH3); 1462.86 (ν alkyls CH2); 1590 - 1615 (ν aryl); 2815 - 2835 (ν O-CH3); 2957.67 (ν alkyls, CH3); 3010 (ν =CH aryl); 3403.97 (ν OH) Third step: The third step is a selective functionalization step of the primary alcohol function. 3.6 g (10.27 mmol) of diol (Va) as prepared in the previous step are dissolved in 15 ml of dry toluene under an inert atmosphere. 12.8 mg (51.37 µmol, 0.5 mol%) of Bu2SnO are added and the resulting mixture is stirred for 1 h. Then, 1.9 ml (12.33 mmol, 1.2 equiv.) of diisopropylethylamine (DIPEA) are added and the resulting mixture is stirred for 5 min. Then, 2.06 g (10.79 mmol, 1.1 equiv.) of tosyl chloride (TsCl) are added and the resulting mixture is stirred for 4 h at room temperature. A yellow aqueous phase appears.A 1M HCl solution is added with vigorous stirring until the pH of the aqueous phase is approximately 1-2. The organic phase is separated and the aqueous phase is extracted twice with 40 ml of DCM. The organic phases are combined, dried over magnesium sulfate and the solvent is evaporated. A crude oil is obtained and purified by silica gel chromatography (eluent: EtOAc / MeOH). The product (VIa) corresponding to (2S,3S)-4-((dimethoxyphosphoryl)oxy)-2-hydroxy-3-((4-methoxybenzyl)oxy)butyl-4-ethylbenzene sulfonate is obtained in the form of a translucent light yellow oil with a yield of 76% (3.95 g, 7.8 mmol). Formula: C21H29O10PS, Molar mass = 504.49 g mol. −1 . NMR 1 H (300.13 MHz, CDCl 3 ), δ (ppm): 2.43 (3H, phenyl-CH 3); 2.92 (1H, OH); 3.70 (m, 1H, CH(OPMB)); 3.72 and 3.76 (s, 3H each, P-OCH3); 3.79 (s, 3H, benzyl OCH3); 3.94 (m, 1H, CH(OH)); 3.99 (2H, CH2(OR)); 4.01-4.15 and 4.17-4.30 (2m, 2*1H, CH2 OP(O)(OCH3)2); 4.40-4.62 (2d, J= 11.1 Hz, 2H, benzyl CH2); 6.85 (d, J = 8.5 Hz, 2H, aromatic CH); 7.20 (d, J= 8.6 Hz, 2H, aromatic CH); 7.32 (d, J= 8.1 Hz, 2H, CH aromatic tosyl group); 7.75 (d, J= 8.2 Hz, 2H, CH aromatic tosyl group). NMR 31 P (121.442 MHz, CDCl3), δ (ppm): 1.48 (P(O)(OMe)2). NMR 13 C (75.49 MHz, CDCl3), δ (ppm): 21.7 (CH3); 54.5 and 54.6 (2d, J= 6.0 Hz, -P(O)(OCH3)2); 55.3 (benzyl OCH3); 65.3 (d, J= 6.0 Hz, CH2- OP(O)(OCH3)2); 68.2 (CH(OH)); 69.9 (CH2(OR)); 72.9 (benzyl CH2); 75.7 (CH(OPMB)); 113.9, 129.7, 130.1 and 159.5 (6C, C aromatic benzyl group); 128.3, 129.8, 132.6 and 146.1 (6C, C aromatic tosyl group). HRMS (ESI+) m / z calcd. For [C21H29O10PS] [M+NH4] + : 522.1563; found: 522.1559. IR (ν cm −1): 814.36 (ν p-disubst. benzene); 843.36 (νSO); 1026.76 (ν P-O-(C)); 1095.72 (ν disubst. alcohol); 1110 - 1140 (ν alkyl ethers); 1174 (ν C=COC); 1244.85 (ν P=O); 1358.05 (ν S=O); 1458.70 (ν alkyls CH2); 1514.14 - 1612.73 (ν aryl); 2815 - 2835 (ν O-CH3); 2957.98 (ν alkyls, CH3); 3010 (ν =CH aryl); 3368.99 (ν OH). Fourth step: The fourth step is a nucleophilic substitution step to replace the tosylate with the azide. 5.7 g (11.3 mmol) of tosylphosphate (VIa) as prepared in the previous step is solubilized in 28 ml of dry dimethylformamide (DMF) under an inert atmosphere. The resulting mixture is stirred and 2.94 g (45.2 mmol, 4 equiv.) of sodium azide is added and the resulting mixture is stirred for 24 h at 50 °C under an inert atmosphere. The product obtained is diluted in chloroform (100 ml), then distilled water is added (60 ml). The dimethyl phosphate (VIIa) is then extracted 3 times with chloroform (150 ml).Dimethyl phosphate is purified by silica gel chromatography (eluent: EtOAc / MeOH). A first quantity of dimethyl phosphate (VIIa) is obtained. The aqueous phase obtained during the extraction of dimethyl phosphate with chloroform contains monomethyl phosphate (VII'a). 100 ml of chloroform are added to the aqueous phase which is then acidified cold with HCl (1M) until reaching a pH equal to 1. The monomethylated phosphate is then extracted from the aqueous phase with chloroform (5*100 ml. The organic phases are combined and dried over MgSO4 then the solvents are evaporated. The monomethylated phosphate is then remethylated by diluting it in methanol and using TMSCHN2 (0.6 M or 2 M in hexane) which is added until the mixture remains yellow and stirred for 30 min. The product obtained (VIIa) does not require purification and represents a second quantity of dimethylated phosphate (VIIa).The first and second quantities of product (VIIa) are combined and correspond to (2S,3S)-4-azido-3-hydroxy-2-((4-methoxybenzyl)oxy)butyl dimethyl phosphate as a translucent light yellow oil with a total yield of 53%. Formula: C14H22N3O7P, Molar mass = 375.31 g. mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 2.67 (1H, OH); 3.25 - 3.43 (2dd, J=12.6 Hz, 6.5 Hz, 2*1H, CH2N3); 3.64 (m, 1H, CH(OPMB)); 3.76 and 3.80 (s, 3H each, POCH3); 3.81 (s, 3H, benzyl OCH3); 3.83 (m, 1H, CH(OH)); 4.05 - 4.19 and 4.20 - 4.31 (2m, 2*1H, CH2OP(O)(OCH3)2); 4.47-4.72 (2d, J=11.2 Hz, 2H, benzyl CH2); 6.88 (d, J = 8.5 Hz, 2H, aromatic CH); 7.28 (d, J = 8.4 Hz, 2H, aromatic CH). NMR 31 P (121.442 MHz, CDCl3), δ (ppm): 1.60 (P(O)(OMe)2). NMR 13 C (75.49 MHz, CDCl3), δ (ppm): 53.1 (CH2N3); 54.6 and 54.7 (2d, J= 6.0 Hz, -P(O)(OCH 3 ) 2 ); 55.3 (benzyl OCH 3 ) ; 65.3 (d, J= 6.0 Hz, (CH 2- OP(O)(OCH3)2); 69.9 (CH(OH)); 73.0 (benzyl CH2); 76.6 (CH(OPMB)); 114.1, 129.5, 130.1 and 159.8 (6C, aromatic C). HRMS (ESI+) m / z calcd. For [C 14 H 22 N 3 O 7 P] [M+NH 4 ] + : 393.1539; found: 393.1529. IR (ν cm −1): 814.36 (ν p-disubst. benzene); 1029.53 (ν PO-(C)); 1177.17 (ν alkyl ethers); 1248.07 (ν P=O); 1459.48 (ν alkyl, CH2); 1514.14 - 1612.84 (ν aryl); 2100.77 (ν azide); 2815-2853 (ν O-CH3); 2957.98 (ν alkyl, CH3); 3010 (ν =CH aryl); 3375.45 (ν OH). Fifth step: The fifth step is an esterification step of the free alcohol function in the sn-1 position with a saturated fatty acid. 324 mg (1.14 mmol, 1.5 equiv.) of stearic acid (VIIIa) are solubilized in 20 ml of dry DCM under an inert atmosphere. Then, 236 mg (1.14 mmol, 1.5 equiv.) of N,N'-dicyclohexylcarbodiimide (DCC) and 93 mg (0.78 mmol, 1 equiv.) of 4-Dimethylaminopyridine (DMAP) are added and the mixture is stirred for 5 min at room temperature under an inert atmosphere. Then, a solution comprising 285 mg (0.76 mmol, 1 equiv.) of azide (VIIa) as prepared in the previous step and 20 ml of dry DCM are added to the mixture.The resulting mixture is stirred for 4 hours at room temperature under an inert atmosphere. Then, the temperature is decreased to 0°C and 15 ml of ethyl acetate are added. The organic phase is washed three times with saturated NaHCO3 solution, dried over MgSO4 and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate). The product (IXa) corresponding to (2S,3S)-1-azido-4-((dimethoxyphosphoryl)oxy)-3-((4-methoxybenzyl)oxy)butan-2-yl stearate is obtained in the form of a white solid with a yield of 50% (230 mg, 0.36 mmol). Formula: C32H56N3O8P, Molar mass = 641.75 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 0.85 (t, J= 6.6 Hz, 3H, CH3; 1.15 - 1.65 (m, 28H, CH 2 ) ; 1.89 (m, 2H, CH 2 (CH 2 )C(O)) ; 2.30 (m, 2H, CH 2C(O)); 3,40 (2dd, J= 12,8 Hz; 6,8 Hz, 2*1H, CH2N3) ; 3,71 et 3,75 (d, 3H chacun, P OCH3) ; 3,75 (s, 3H, benzyl OCH3) ; 3,77 (m, 1H, CH(OPMB)) ; 4,08 - 4,11 (m, 2H, CH 2 OP(O)(OCH 3 ) 2 ) ; 4,49-4,67 (2d, J= 11,2 Hz, 2H, benzyl CH 2 ) ; 5,14 (m, 1H, CH(OC(O)CH2) ; 6,86 (d, J = 8,8 Hz, 2H, CH aromatique) ; 7,24 (d, J= 8,6 Hz, 2H, CH aromatique). RMN 31 P (121,442 MHz, CDCl3), δ (ppm) : 1,22 (P(O)(OMe)2). RMN 13 C (75,49 MHz, CDCl3), δ (ppm) : 14,17 (CH3) ; 22,76 - 34,02 (15C, CH2) ; 34,2 (CH2C(O)) ; 50,26 (CH2N3) ; 54,5 and 54,6 (2d, J= 6,0 Hz, -P(O)-(OCH3)2) ; 55,3 (benzyl OCH3) ; 66,7 (d, J= 6,0 Hz, (CH2OP(O)(OCH3)2) ; 70,9 (CH(OC(O)CH2) ; 72,9 (benzyl CH2) ; 75,4 (CH(OPMB)) ; 114,0 , 129,4 , 129,8 et 159,6 (6C, C aromatique) ; 173,0 (OC(O)CH2). HRMS (ESI+) m / z calcd. Pour [C32H56N3O8P] [M+ Na] + : 664,3703 ; trouvée : 664.3702. IR (ν cm −1): 850.03 (ν p-disubst. benzene); 1039.63 (ν PO-(C)); 1157.17 (ν CO); 1276.71 (ν P=O); 1459.48 (ν alkyls, CH2); 1514.14 - 1612.84 (ν C=C aryl); 1745.17 (ν C=O); 2101.25 (ν azide); 2853.16 (ν O-CH3); 2923.78 (ν alkyls, CH3). Sixth step: The sixth step is a deprotection step of the paramethoxybenzyl (PMB) group followed by an esterification step of the free alcohol function in the sn-2 position with an unsaturated fatty acid. 185 mg (0.290 mmol) of stearic azide (IXa) as prepared in the previous step are solubilized in 6 ml of dry DCM under an inert atmosphere. Then, 338 µL of aqueous phosphate buffered saline (PBS) (pH 7.2) containing 0.15 M NaCl are added. 325.95 mg (1.45 mmol, 5 equiv.) of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added at 0°C under an inert atmosphere for 5 h. Then, the reaction medium is diluted with 6 ml of cold DCM and 5 ml of cold saturated NaHCO3 solution. The resulting mixture becomes dark green.The aqueous phase is extracted twice with 20 ml of cold DCM, and the organic phases are combined and washed with 20 ml of saturated NaHCO3 solution, dried over MgSO4 and the solvents are evaporated under reduced pressure. The obtained alcohol (Xa) is in the form of an orange-yellow oil. 162 mg (0.65 mmol, 1.5 equiv.) of oleic acid (XIa) are solubilized in 7 ml of dry DCM under an inert atmosphere at 0°C. Then, 89 mg (0.44 mmol, 1.5 equiv.) of DCC and 36 mg (0.29 mmol, 1 equiv.) of DMAP are added and the resulting mixture is stirred for 5 min at room temperature under an inert atmosphere. Then, a solution comprising 152 mg (0.290 mmol, 1 equiv.) of the alcohol (Xa) obtained in the previous step and 7 ml of dry DCM under an inert atmosphere is added at 0°C to said mixture. The resulting mixture is stirred for 5 h at 0°C under an inert atmosphere. Then, 10 ml of ethyl acetate is added.The organic phase is washed three times with saturated NaHCO3 solution, dried over MgSO4 and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate). The product (XIIa) corresponding to (2S,3S)-4-azido-1-((dimethoxyphosphoryl)oxy)-3-(stearoyloxy)butan-2-yl oleate is obtained in the form of a translucent white-clear oil with a yield of 50% (111 mg, 0.15 mmol). Formula: C42H80N3O8P, Molar mass = 786.07 g mol. −1 . NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 0.86 (t, J= 6.6 Hz, 6H, 2*CH3); 1.25 (m, 48H, CH2); 1.61 (m, 2*2H, CH2CH2C(O)O); 2.00 (m, 4H, CH2CH=CHCH2); 2.32 - 2.38 (m, 2*2H, CH2C(O)O); 3.39 - 3.45 (dd, J=13.2 Hz; 5.4 Hz, 1H, CH2N3); 3.47 - 3.53 (dd, J= 13.2 Hz; 3.6 Hz, 1H, CH2N3); 3.73 and 3.78 (d, 3H each, P-OCH3); 4.15 - 4.18 (m, 2H, CH2OP(O)(CH3)2); 5.27 (m, 2*1H, 2*CH(OC(O)CH2); 5.32 (m, 2H, CH=CH). NMR 31P (121.442 MHz, CDCl3), δ (ppm) : 1.10 (P(O)(OMe)2). NMR 13 C (75.49 MHz, CDCl3), δ (ppm): 14.17 (2*CH3); 22.70 (2*CH2CH3); 24.82 (2*CH2CH2C(O)O); 27.34 (CH2CH=CHCH2) ; 29.12 - 31.94 (22C, CH2); 34.08 (2*CH2C(O)); 50.64 (CH 2 N 3 ); 54.54 and 54.62 (2d, J= 6.0 Hz, -P(O)-(OCH3)2); 65.10 (d, J= 6.0 Hz, CH2 OP(O)(OCH3)2) ; 69.69 (CH(OC(O)CH2 stearic) ; 70.10 (CH(OC(O)CH 2 oily); 130.06, 129.67 (CH 2 CH CHCH 2 ); 172.7 (2*OC(O)CH2). HRMS (ESI+) m / z calcd. For [C42H80N3O8P] [M+ H] + : 786.5761 ; found: 786.5759. IR (ν cm −1): 722.15 (ν Z CH=CH); 1039.63 (ν PO-(C)); 1157.46 (ν CO); 1276.71 (ν P=O); 1464.53 (ν alkyls, C); 1745.17 (ν C=O); 2101.75 (ν azide); 2853.31 (ν O-CH3); 2922.63 (ν alkyls, CH3) Seventh step: The seventh step is a deprotection step of the phosphate head. 50 mg (0.64 µmol) of diester phosphate (XIIa) as prepared in the previous step are solubilized in 3 ml of CDCl3 previously neutralized with K2CO3 and the resulting solution is stored on molecular sieve under an inert atmosphere. Then, 21 µL (160 µmol, 2.5 equiv.) of bromotrimethylsilane (TMSBr) is added and the resulting mixture is stirred for 5 h at room temperature under a neutral atmosphere. 1 ml of water (H2O) is added and the solvents are evaporated. The crude product is purified by silica gel chromatography (water / methanol, C18AQ column marketed by Interchim).Product (Ia) corresponding to (2S,3S)-4-azido-2-(oleoyloxy)-3-(stearoyloxy)butyl hydrogen phosphate (modified PA 18:1-18:0) is obtained in the form of a clear-white oil with a yield of 31% (15 mg, 0.198 µmol). Formula: C40H75N3O8P. – , Molar mass = 757.07 g mol −1 Example 2: synthesis of LPG (Ib) 330 mg (0.51 mmol) of stearic azide as prepared in Example 1 is solubilized in 10 ml of dry DCM under an inert atmosphere. Then, 550 µL of aqueous phosphate buffered saline (PBS) (pH 7.2) comprising 0.15 M NaCl is added. 530 mg (2.55 mmol, 5 equiv.) of DDQ is added at 0°C under an inert atmosphere for 6 h. Then, the reaction medium is diluted with 10 ml of cold DCM and 10 ml of cold saturated NaHCO3 solution. The resulting mixture turns dark green. The aqueous phase is extracted twice with 40 ml of cold DCM, and the organic phases are combined and washed with 40 ml of cold saturated NaHCO3 solution, dried over MgSO4, and the solvents are evaporated under reduced pressure. The alcohol obtained is in the form of a yellow-orange oil. 283 mg (1.02 mmol, 2 equiv.) of linoleic acid are solubilized in 5 ml of dry DCM under an inert atmosphere at 0°C. Then, 159 mg (0.78 mmol, 1.5 equiv.) of DCC and 63 mg (0.52 mmol, 1 equiv.) of DMAP are added and the resulting mixture is stirred for 5 min at room temperature under an inert atmosphere. Then, a solution comprising 266 mg (0.52 mmol, 1 equiv.) of the alcohol obtained in the previous step and 5 ml of dry DCM under an inert atmosphere is added at 0°C to said mixture. The resulting mixture is stirred for 5 h at 0°C under an inert atmosphere. Then, 15 ml of ethyl acetate are added. The organic phase is washed three times with a saturated solution of NaHCO3, dried over MgSO4 and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate). The product corresponding to (2S,3S)-4-azido-1-((dimethoxyphosphoryl)oxy)-3-(stearoyloxy)butan-2-yl oleate is obtained in the form of a light yellow translucent oil with a yield of 50% (200 mg, 0.26 mmol). Formula: C42H78N3O8P, Molar mass = 784.07 g mol. −1 . NMR 1H (300,13 MHz, CDCl3), δ (ppm) : 0,92 (t, J= 6,6 Hz, 6H, 2*CH3) ; 1,30 (m, 44H, CH2) ; 1,67 (m, 2*2H, CH2CH2C(O)O) ; 2,08 (m, 4H, CH2CH=CHCH2) ; 2,35 - 2,40 (m, 2*2H, CH 2 C(O)O) ; 3,43 - 3,48 (dd, J= 13,2 Hz ; 5,4 Hz, 1H, CH2N3) ; 3,53 - 3,57 (dd, J= 13,2 Hz ; 3,6 Hz, 1H, CH2N3) ; 3,72 et 3,78 (d, 3H chacun, POCH3) ; 4,12 - 4,23 (m, 2H, CH2OP(O)(CH3)2) ; 5,31 (m, 2*1H, 2*CH(OC(O)CH 2 ) ; 5,37 - 5,40 (m, 4H, CH=CH). RMN 31 P (121,442 MHz, CDCl3), δ (ppm) : 1,08 (P(O)(OMe)2). RMN 13C (75.49 MHz, CDCl3), δ (ppm): 14.07 and 14.12 (2*CH3); 22.58 and 22.70 (2*CH2CH3); 24.82 and 24.84 (2*CH2CH2C(O)O); 27.21 (CH2CH=CHCH2); 29.12 - 31.94 (22C, CH2); 34.07 (2*CH2C(O)); 50.64 (CH2N3); 54.55 and 54.63 (2d, J=6.0 Hz, -P(O)-(OCH3)2); 65.16 (d, J=6.0 Hz, CH2OP(O)(OCH3)2); 69.69 (CH(OC(O)CH2 stearic); 70.01 (CH(OC(O)CH2 linoleic); 127.89, 128.12, 129.96 and 130.23 (CH2CH=CHCH2); 172.68 and 172.70 (2*OC(O)CH2). HRMS (ESI+) m / z calcd. For [C42H78N3O8P] [M+ Na] +: 806.5424; found: 806.5426. 50 mg (0.64 µmol) of diester phosphate (XIIb) as prepared in the previous step are solubilized in 3 ml of CDCl3 previously neutralized with K2CO3 and the resulting solution is stored on molecular sieve under an inert atmosphere. Then, 21 µL (160 µmol, 2.5 equiv.) of bromotrimethylsilane (TMSBr) are added and the resulting mixture is stirred for 5 h at room temperature under a neutral atmosphere. 1 ml of water (H2O) is added and the solvents are evaporated. The crude product is purified by silica gel chromatography (water / methanol, C18AQ column marketed by Interchim). The product (Ib) corresponding to (2S,3S)-4-azido-2-(linoleoyloxy)-3-(stearoyloxy)butyl hydrogen phosphate (modified PA 18:2-18:0) is obtained in the form of a clear-white oil with a yield of 31% (15 mg, 0.198 µmol). Formula: C40H73N3O8P – , Molar mass = 755.07 g mol −1Example 3: Synthesis of a fluorescent probe GPL (XIVa) from GPL (Ia) . 33.09 mg (0.1663 mmol) of 4-chloro-7-nitrobenzo[c][1,2,5]oxadiazole (NBDCl) are added to a solution of 132 mg (0.415 mmol, 2.5 equiv.) of cyclooctyne (ADIBO C6 amine) in 5 ml of MeOH. 140 µL (0.832 mmol, 5 equiv.) of DIPEA are added and the resulting mixture is stirred for 2 h at room temperature. Then, the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: CH2Cl2 / MeOH). The product (XVa) corresponding to 1-(11,12-didehydrodibenzo[b,f]azocin-5(6H)-yl)-6-((7-nitrobenzo[c][1,2,5]oxadiazol-4- yl)amino)hexan-1-one (ADIBO-NBD) is obtained in the form of a fluorescent green-yellow oil with a yield of 57% (45 mg, 94 µmol). Formula: C27H23N5O4, Molar mass = 481.18 g mol −1 . NMR 1H (300.13 MHz, CDCl3), δ (ppm): 1.21 – 1.23 (m, 2H); 1.25 – 1.42 (m, 4H); 1.94 – 2.01 (m, 2H); 2.21 – 2.30 (m, 2H); 3.65 – 3.70 (d, J= 13.8 Hz, 1H); 5.17 – 5.22 (d, J= 13.8 Hz, 1H); 6.04 – 6.07 (d, J= 8.7 Hz, 1H); 7.26 – 7.42 (m, 4H); 7.70 – 7.72 (dd, J = 7.2 Hz; 1.3 Hz, 1H); 8.40 – 8.50 (dd, J= 8.7 Hz; 3.5 Hz, 1H). 10 mg (0.0132 mmol) of ADIBO-NBD (XVa) as prepared in the previous step in 1 ml of CDCl3 are added to a solution comprising 25.4 mg (0.0527 mmol, 4 equiv.) of GPL Ia as prepared in Example 1 and 3 ml of CDCl3. The resulting mixture is stirred for 1 h at 40°C. The solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silica gel (eluent: H2O / MeCN).The product (XIVa) corresponding to (2S,3S)-4-(8-(6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl) amino)hexanoyl)-8,9- dihydro-1H-dibenzo[b,f][1,2,3]- triazolo[4,5-d]azocin-1-yl)-1- (phosphonooxy)-3-(stearoyloxy)butan-2-yl oleate is obtained in the form of a fluorescent green-yellow oil with a yield of 90% (14.7 mg, 12 µmol). Formula: C67H99N8O12P, Molar mass = 1238.71 g mol. −1. HRMS (ESI-) m / z calcd. For [C67H98N8O12P] [MH]-: 1237.7047; found: 1237.7104. Example 4: Use of GLP (Ia) and (Ib) as molecular tools In this example, the interaction between GPL (Ia) or (Ib) and a phosphatidic acid (PA) mobilizing protein, the Spo20p-GFP protein expressed in the target cells and which is fluorescent in the green, is highlighted. To do this, GPL (Ia), and, for comparison, a natural GPL PA 18:1-18:0 (hereinafter referred to as GPL C1) marketed under the reference 840861C by Avanti Polar Lipids, are incubated for 5 min at a concentration of 100 µM, with PC12 cells expressing Spo20p-GFP. The cell medium without GPL is used as a control (hereinafter referred to as C1). Under these control conditions, Spo20p-GFP is mainly found in the nucleus and cytoplasm of the cells.Similarly, GPL (Ib), and, for comparison, a natural GPL PA 18:2-18:0 (hereinafter referred to as GPL C2) marketed under the reference 840862C by Avanti Polar Lipids are incubated for 5 min at a concentration of 100 µM, with PC12 cells expressing Spo20p-GFP. The cell medium without GPL is used as a control (hereinafter referred to as C2). Figure 1 shows confocal microscopy images obtained using a device sold under the trade name SP5II by the company Leica, of the two control media C1 and C2 (Figures 1 a and 1 d respectively), of the medium after incubation with the comparative GPL C1 (Figure 1 b), of the medium after incubation with the GPL (Ia) of the invention (Figure 1 c), of the medium after incubation with the comparative GPL C2 (Figure 1 e), and of the medium after incubation with the GPL (Ib) of the invention (Figure 1 f).As can be seen in Figure 1, the GPLs (Ia) and (Ib) of the invention lead to recruitment of the Spo20p-GFP protein to the plasma membrane of PC12 cells in the same way as the corresponding natural GPLs GPL C1 and GPL C2. This indicates that the GPLs of the invention reproduce two important characteristics of natural PAs, namely to insert themselves into the plasma membrane by accessing the inner leaflet and to recruit the Spo20p-GFP protein there. A marker hereinafter called Membright (obtained from Mayeul Collot UMR- 7021, Strasbourg) is incubated for 5 minutes on the cells in the media as prepared above to specifically label the plasma membrane of the cells. Figure 2 shows the percentage of colocalization of the Spo20p-GFP protein and different GPLs in the plasma membrane, said percentage being determined using Image J software.Therefore, thanks to the synthetic GPL (I) of the invention, it is possible to locate and identify the different proteins that interact with them. Example 5: Use of GPL (XIVa) as a molecular tool In this example, the interaction between GPL (XIVa) which fluoresces in the green (thanks to the nitrobenzoadiazole-based fluorophore) and a phosphatidic acid (PA) mobilizing protein, the CgA-AF633 protein which is fluorescent in the red, is highlighted.To do this, giant liposomes composed of 96% by mass of dioleoylphosphatidylcholine (DOPC) and 4% by mass of GPL (XIVa), and for comparison giant liposomes composed of 96% by mass of dioleoylphosphatidylcholine (DOPC) and 4% by mass of a natural GPL modified with a nitrobenzoadiazole-based fluorophore: PA 18:1–6:0 NBD marketed under the reference 810175C by Avanti Polar Lipids, at a concentration of 1 mM, are prepared using the polyvinyl alcohol assisted swelling method (well known as the “PVA assisted swelling method” as described in Carmon et al., FASEB J., 2020, 34:6769–6790). Figure 3 shows light microscopy images of liposomes containing commercial GPL PA 18:1–6:0 NBD (Figure 3 a) and liposomes containing GPL (XIVa) of the invention (Figure 3 b).Figure 4 shows images obtained using a confocal microscope sold under the trade name SP5 by the company Leica, of a liposome containing the commercial GPL PA 18:1–6:0 NBD (Figure 4 a) and liposomes containing the GPL (XIVa) of the invention (Figure 4 b), thus indicating that the GPL (XIVa) of the invention participates in the formation of giant liposomes. CgA, made fluorescent in the red due to its coupling with the fluorophore Alexa 633 or AF633 (CgA-AF633), is incubated at a concentration of 4 µM with the liposomes as prepared above. Figure 5 shows confocal microscope images of liposomes containing commercial GPL PA 18:1–6:0 NBD incubated with CgA-AF633 protein (Figures 5 a, 5 b, 5 c) and liposomes containing GPL (XIVa) of the invention incubated with CgA-AF633 protein (Figures 5 d, 5 e, 5 f).In Figures 5 a and 5 d, the excitation wavelength is 463 nm and the detection wavelength is 539 nm to visualize the green-fluorescent GPLs; in Figures 5 b and 5 e, the excitation wavelength is 633 nm and the detection wavelength is 648 nm to visualize the red-fluorescent CgA-AF633 protein; Figures 5 c and 5 f result from the superposition of Figures 5a and 5b and then Figures 5 d and 5 e, respectively, in order to visualize both the green-fluorescent GPLs and the red-fluorescent CgA-AF633 protein. While incubation does not result in any interaction of the CgA-AF633 protein with liposomes containing the commercial GPL PA 18:1–6:0 NBD, it does result in membrane deformations of liposomes containing the inventive GPL (XIVa) (white arrows). Furthermore, the CgA-AF633 protein only interacts with liposomes containing GPL (XIVa).The interaction of CgA-AF633 with liposomes is manifested by yellow fluorescence, particularly at the level of membrane deformations (Figure 5 f). This indicates that the GPL of the invention reproduces two important characteristics of natural PA, namely interacting with the CgA protein and allowing membrane deformation. Therefore, thanks to the synthetic GPL (XIVa) of the invention, it is possible to locate and identify proteins such as CgA that interact with it. Example 6: Synthesis of a fluorescent probe GPL (XIVa') from GPL (Ia). . 50 mg (66 µmol) of compound (Ia) as prepared in Example 1 was solubilized in 330 µl of freshly distilled pyridine. 50.5 mg (330 µmol, 5 equivalents) of o-nitrobenzyl alcohol and 330 µl (3.29 mmol, 50 equivalents) of trichloroacetonitrile were added. The reaction was sealed with a Teflon septum and irradiated for 60 min at 90°C (maximum power of 120W). Then, the solvent was evaporated in vacuo and the crude product was purified by silica gel chromatography (eluent: CHCl3 / isopropanol) to give an intermediate compound as an oil with a yield of 31% (18.3 mg. HRMS (ESI-) m / z calcd. For [C47H81N4O10P] [MH]-: 891.5609; found: 891.5612. To a solution of the intermediate compound prepared in the previous step (5 mg, 5.60 µmol) in 0.5 µl of CDCl3 was added 10.8 mg (22.4 µmol, 4 equiv.) of ADIBO-NBD as prepared in Example 3 (compound XVa) in 0.5 ml of CDCl3 and the mixture was stirred for 4 h at 40 °C.The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (eluent: CDCl3 / i-PrOH). The product (XIVa') was obtained as a yellow-green fluorescent oil with a yield of 32 (2.2 mg). This compound comprises, compared to compound (XIVa), a photoactivatable group OR'. 1 as defined in the invention on the polar head. HRMS (ESI-) m / z calcd. For [C74H103N9O14 P] [MH]-: 1372.7368; found: 1372.7371. Example 7: Synthesis of a fluorescent probe GPL (XIVa-2) from GPL (Ia) The carboxylic acid “ATTO 746N” (5.00 mg, 6.70 µmol) was dissolved in dichloromethane (150 µl). Then, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (2.50 mg, 16.1 µmol) and the amine ADIBO C6 (4.70 mg, 14.7 µmol) were added and the mixture was stirred at room temperature for 2 hours. Then, 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate or TBTU (3.23 mg, 10.1 µmol) and N,N-diisopropylethylamine (DIPEA, 1.75 µl, 10.1 µmol) were added. After 1 h, the reaction was complete. The solvent was removed under reduced pressure. This crude product of formula (XVa-2) was used in the next step without purification. The crude product (XVa-2) (6.33 mg, 6.7 µmol) and LPG Ia as prepared in Example 1 (7.99 mg, 10.6 µmol) were solubilized in CHCl3. After 1 day, the solvent was removed under reduced pressure.The crude product is purified by silica gel chromatography (eluent: gradient of 5% methanol to 20% in CH2Cl2, column “Viridis Silica 5µ, 150 x 4.60 mm) to give a blue solid (XIVa-2) (5 mg, yield of 38% after 2 steps). HRMS (ESI+) m / z calcd. For [C103H148N8O11 P] [M+H]. + : 1704.1000; found: 1704.1035. Example 8: Synthesis of a fluorescent probe GPL (XIVa-3) from GPL (Ia) . Compound (XIIa) as prepared in Example 1 (83 mg, 106 mmol, 1 equiv) and 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one (52.8 mg, 264 µmol, 2.5 equiv) were solubilized in tetrahydrofuran (THF) (4 mL). Copper sulfate pentahydrate (59.0 mg, 370 µmol, 3.5 equiv) and sodium ascorbate (151 mg, 760 µmol, 7.2 equiv) were added with water (1 mL). The solution was stirred at room temperature overnight. The solvents were removed under reduced pressure. The crude product was purified by silica gel chromatography with solid deposition (celite) and an eluent: gradient of 60% ethyl acetate in cyclohexane) to obtain the intermediate compound phosphonate diester in the form of a brown solid with a yield of 66% (104 mg). Molar mass = 970.5927 g mol −1 . NMR 1H (300,13 MHz, CDCl3), δ (ppm) : 7,71 (s, 1H, CH triazole), 7,62 (d, 1H, J = 9,5 Hz, CH coum), 7,37 (m, 1H, CH coum), 6,90 (m, 2H, CH coum), 6,27 (d, 1H, J = 9,5 Hz, CH coum), 5,56 (m, 1H, J = 5,3 Hz, CH squelette glycérol), 5,33 (m, 2H, CH double liaisons), 5,24 (s, 2H, CH2 benz coum), 5,17 (m, 1H, CH squelette glycérol), 4,61 (d, 2H, J = 5,8 Hz, CH2 benz triazole), 4,21 (m, 2H, CH2OP), 3,78 (d, 3H, J = 2,9 Hz, POCH3), 3,74 (d, 3H, J = 2,8 Hz, POCH3), 2,36 (m, 2H*2, CH2CO2), 2,01 (d, 2H*2, , J = 6,1 Hz, CH2CH=CHCH2), 1,57 (dt, 2H*2, J = 33,7 Hz / 7,1 Hz, CH2CH2CO2), 1,24 (s, 48H, CH2 chaines grasses), 0,87 (t, 6H, J = 7 Hz, CH3*2). RMN 31 P (121,442 MHz, CDCl3), δ (ppm) : 1,08 (P(O)(OMe)2). RMN 13 C (75,49 MHz, CDCl3), δ (ppm) : 172,8 (CO ester), 172,5 (CO ester), 161,4 (Cq O éther), 161,2 (CO ester coum), 155,9 (Cq alpha O ester coum), 143,5 (Cq triazole), 143,0 (Car), 130,2 (double liaison), 129,8 (double liaison), 129,0 (C ar), 123.9 (CH triazole), 113.6 (C ar ), 113.2 (Cq ar ), 112.8 (C ar ), 102.3 (Car), 69.8 (CH glycerol alpha ester next to phosphorus, J = 7.6 Hz), 69.2, (CH glycerol alpha ester away from phosphorus), 64.9 (CH2 alpha OP, J = 5.2 Hz), 62.3 (CH 2 benz coum), 54.8 (2 CH 3 OP, J = 6.6 Hz), 50.3 (CH 2 alpha triazole), 34.1 (CH2 alpha ester), 34.0 (CH2 alpha ester), 32.0 – 22.8 (CH2 fatty chain), 14.2 (CH3). HRMS (ESI-) m / z calcd. Found: 970.5934. The intermediate compound as obtained above (90 mg, 91.1 µmol, 1 equivalent) was solubilized in CDCl3 (5 ml) previously neutralized on K2CO3 and stored on a molecular sieve under neutral atmosphere. Then, freshly distilled TMSBr (69.7 mg, 455 µmol, 5 equivalents) was added and the mixture was stirred for 5 h at room temperature under neutral atmosphere. After monitoring by NMR 31P, the reaction was quenched with MeOH and evaporated under reduced pressure to obtain a crude product as a brown oil (XVa-3) (95 mg, quantitative yield). NMR 1 H (300.13 MHz, CDCl3), δ (ppm): 8.60 (s, 1H, CH triazole), 7.65 (s, 1H, CH coum), 7.37 (s, 1H, CH coum), 6.92 (s, 2H, coum), 6.21 (s, 1H, coum), 5.68 (s, 1H, CH skeleton glycerol), 5.54 – 5.17 (m, 2*1H + 2H + 2H, CH=CH + CH2 benz coum + CH2 benz triazole), 4.96 (m, 1H, CH glycerol skeleton), 4.25 (d, 2H, J = 31.7 Hz, CH2OP), 2.30 (m, 2*2H, CH2CH2CO2), 1.98 (m, 2*2H, CH2CH=CHCH2), 1.49 (d, 2*2H, J = 27.9 Hz, CH2CH2CO2), 1.24 (s, 48H, CH2 fatty chains), 0.87 (t, 6H, J = 6.5 Hz, CH3). NMR 31 P (121.442 MHz, CDCl3), δ (ppm): -0.94 ppm. Example 9: synthesis of a GPL fluorescent probe (XIVa-4) from GPL (Ia) The compound of formula (XIVa-3) as prepared in Example 8 (95 mg, 99.5 µmol, 1 equivalent) was solubilized in pyridine (450 µl), then N-trityleethanolmine (151 mg, 497 µmol, 5 equivalents) and trichloroacetonitrile (450 µl) were added. The reaction mixture was heated at 90°C for 1 hour under microwave. The crude product obtained was purified by silica gel chromatography with liquid deposition (dichloromethane) and an eluent (gradient of 100% ethyl acetate to 100% isopropanol) to obtain the intermediate compound in the form of a brown solid with a yield of 92% (114 mg). Molar mass = 1241.7288 g / mol NMR 1H (300,13 MHz, CDCl3), δ (ppm) : 7,78 (s, 1H, CH triazole), 7,51 (m, 8H, 2CH coum + CH trityl), 7,26 (m, 9H, CH trityl), 6,82 (m, 2H, CH coum), 6,20 (d, 1H, J = 9,4 Hz, CH coum), 5,58 – 4,90 (m, 2H + 1H*2 + 2H, CH2 benz coum + 2CH double liaisons + CH2 benz triazole), 4,56 (m, 2H, 2CH squelette glycérol), 4,22 – 3,70 m, 2H*2 + 1H*2, NCH2CH2OP + 2CH2OP), 3,01 (s, 1H, NH), 2,32-2,07 (m, 4H, CH2CO2), 1,98 (m, 2H*2, CH2CH=CHCH2), 1,64 (m, 2H*2, CH2CH2CO2), 1,25 (m, 48H, CH2 chaines grasses), 0,87 (m, 6H, CH3*2) RMN 13C (75.49 MHz, CDCl3), δ (ppm): 172.8 (CO ester), 172.3 (CO ester), 161.4 (Cq O ether), 161.2 (CO ester coum), 155.7 (Cq alpha O ester coum), 143.4 (CHar), 142.5 (Cq triazole), 130.1 (CH double bond fatty chain), 129.6 (CH double bond fatty chain), 129.4 – 128 (CHar trityl + CHar coum + CHa triazole), 113.4 (CHar), 113.0 (Cqar), 112.8 (CHar), 102.1 (CHar), 74.6 (Cq trityl), 70.4 (CH glycerol skeleton next to phosphorus), 69.5 (CH glycerol skeleton distant from phosphorus), 63.7 (CH2 alpha OP, J = 5.2 Hz), 62.1 (CH2 benz coum), 58.8 (CH 2 O ethanolamine), 50.0 (CH 2 benz triazole), 49.2 (CH 2 N ethanolamine), 34.0 / 34.1 (CH2 alpha ester), 32.0 - 22.8 (CH2 fatty chain), 14.2 (CH3). NMR 31P (121.442 MHz, CDCl3), δ (ppm): 2.01 ppm. HRMS (ESI-) m / z calcd. Found: 1241.7233. The intermediate compound as prepared in the previous step (10 mg, 8.05 µmol, 1 equivalent) in 0.2 mL of anhydrous dichloromethane, and triethylsilane (3.74 mg, 32.2 µmol, 4 equivalents) in 0.1 mL of dry dichloromethane were added to a 1 mL vial under argon atmosphere. Then, trifluoroacetic acid (3.67 mg, 32.2 µmol, 4 equivalents) in 0.1 mL of dry dichloromethane was added to the mixture. The reaction turned yellow upon addition of the acid, and was stirred for 3 h at room temperature. The reaction was monitored by UPLC (“Phenomenex Kinetex” 2.6µ PFP 100Å 150 x 4.60 mm) with a UV detector (at 254 nm) to follow the appearance of the free trityl group at 8.72 min) and a fluorescent detector (at 320 nm) to follow the transition from the intermediate compound at 12.4 min to the product (XIVa-5) at 12.2 min. Molar mass = 999.6193 g mol −1. HRMS (ESI-) m / z calcd. Found: 999.6179.

Claims

Claims 1. Synthetic glycerophospholipid corresponding to the following formula (I): in which: * the OR group 1 is chosen from a hydroxyl group, a choline remnant, an ethanolamine remnant, a glycerol remnant, a serine remnant, an inositol remnant, an inositol monophosphate remnant, an inositol bisphosphate remnant, an inositol trisphosphate remnant, a glycerophosphate remnant, a glucose remnant, an inositolglycan remnant, and a remnant of any hydroxylated compound capable of forming a phosphodiester group in the sn-3 position belonging to a subclass of natural GPLs, * R 2 represents an unsaturated aliphatic chain, mono- or polyunsaturated, comprising at least 14 carbon atoms, and * R 3 represents a saturated aliphatic chain comprising at least 10 carbon atoms.

2. Glycerophospholipid according to claim 1, characterized in that R 3represents a saturated aliphatic chain comprising 14 to 30 carbon atoms.

3. Glycerophospholipid according to claim 1 or 2, characterized in that R 2 represents an unsaturated aliphatic chain, mono- or polyunsaturated, comprising from 16 to 24 carbon atoms.

4. Glycerophospholipid according to any one of the preceding claims, characterized in that the unsaturated aliphatic chain comprises from 1 to 6 unsaturations.

5. Glycerophospholipid according to any one of the preceding claims, characterized in that it is selected from the compounds of formulas (Ia) to (Ie) shown in the following table:

6. A process for preparing a glycerophospholipid of formula (I) as defined in any one of claims 1 to 5, characterized in that it comprises at least the following steps: i) a step for preparing a phosphotriester of formula (IV) comprising a diacetal function implementing the functionalization of a diacetal derivative of (2S,3S)-butane-1,2,3,4-tetrol corresponding to formula (III) with a dialkyl halogenophosphate of formula (IV) in basic medium, according to the following scheme: , in which R 4 represents a C1-C5 alkyl group or a benzyl group, and R 5 represents an alkyl group in C1-C5, ii) a deprotection step in acidic medium of the diacetal function of the phosphotriester of formula (IV) to form a diol of formula (V) comprising a primary alcohol, according to the following scheme: , iii) a step of selective functionalization of the primary alcohol of the diol of formula (V) to form a monoalcohol of formula (VI) comprising a primary alcohol modified by an R group 6 , according to the following scheme: in which R 6 is chosen from the following groups: tosyl, mesyl, and triflate, iv) a nucleophilic substitution step of the OR function 6 of the monoalcohol of formula (VI) to form an azide of formula (VII) comprising an alcohol function, according to the following scheme: , v) an esterification step of the alcohol function of the azide of formula (VII) with a saturated fatty acid of formula (VIII) to form an azide of formula (IX) comprising a saturated fatty acid chain and an alcohol function protected by a paramethoxybenzyl group, according to the following scheme: , in which R 3is as defined in claim 1, 2 or 5, vi) a step comprising a substep vi-1) of deprotection of the paramethoxybenzyl group of the azide of formula (IX) to form an azide of formula (X) comprising an alcohol function, followed by a substep vi-2) of esterification of the alcohol function of the azide of formula (X) with an unsaturated fatty acid of formula (XI), to form an azide of formula (XII) comprising a saturated fatty acid chain, an unsaturated fatty acid chain, and a phosphotriester function, according to the following scheme: , in which R 2 is as defined in claim 1, 3, 4 or 5, and vii) a step of deprotection of the R groups 4 to form a compound of formula (I) in which OR 1 = OH, possibly followed by a step of preparing a compound of formula (I) in which OR 1≠ OH.

7. A process according to claim 6, characterized in that step iii) is carried out in the presence of tosylate chloride, a base, and a tin-based catalyst.

8. A process according to claim 6 or 7, characterized in that substep vi-1) is carried out in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and at a temperature ranging from -20°C to 50°C.

9. A modified glycerophospholipid corresponding to the following formula (XIV): in which: * OR' 1 represents a group OR 1 as defined in any one of claims 1 or 5, or a photoactivatable group, * R 2 and R 3 are as defined in any one of claims 1 to 5, and * R 8 and R 9 Independently of each other, these are chosen from a fluorophore group, a photocurable group, a radiolabeling group, and a hydrogen atom; or the R groups 8 and R 9together form a group selected from a fluorophore group, a photocrosslinkable group, and a radiolabel group.

10. A process for preparing a modified glycerophospholipid of formula (XIV) as defined in claim 9, characterized in that it comprises at least one step A) of contacting a synthetic glycerophospholipid of formula (I) as defined in any one of claims 1 to 5 or obtained according to a process as defined in any one of claims 6 to 8, with an alkyne corresponding to the following formula (XV): in which R 8 and R 9are as defined in claim 9.

11. A method according to claim 10, characterized in that step A) is carried out after contacting the synthetic glycerophospholipid (I) with a biological medium, and the method further comprises, prior to step A), a step a) of contacting the synthetic glycerophospholipid (I) with a biological medium, in particular in vitro or ex vivo.

12. Use of a synthetic glycerophospholipid of formula (I) as defined in any one of claims 1 to 5 or obtained according to a method as defined in any one of claims 6 to 8; or of a modified glycerophospholipid (XIV) as defined in claim 9 or obtained according to a method as defined in any one of claims 10 or 11, as a molecular tool, or as a biological probe. 13.Use of a synthetic glycerophospholipid of formula (I) as defined in any one of claims 1 to 5 or obtained by a process as defined in any one of claims 6 to 8; or of a modified glycerophospholipid of formula (XIV) as defined in claim. 9 or obtained by a process as defined in any one of claims 10 or 11, as an in vitro or ex vivo diagnostic tool.

14. Synthetic glycerophospholipid of formula (I) as defined in any one of claims 1 to 5 or obtained by a process as defined in any one of claims 6 to 8; or modified glycerophospholipid of formula (XIV) as defined in claim 9 or obtained by a process as defined in any one of claims 10 or 11, for its medical use.

Images